SYNTHESIS AND BIOLOGICAL EVALUATION OF C-DISACCHARIDES

一种合成“C-二糖”的方法学的发展 具有亚甲基(CH2)的未知类别的假二糖 而不是糖苷间键上的氧原子，并且 研究它们的生物学特性是主要目标。 这项拟议的研究。由于他们对尊重完全无动于衷 对于水解，这些假二糖是非常有趣的 天然双糖的类似物，有望发挥强大的作用 糖基水解酶的竞争性抑制剂。如图所示 包括S二糖、糖苷酶抑制剂在内的碳水化合物衍生物 不仅是有用的生化工具，而且发现也很重要 生理学在治疗和研究中的应用 代谢性疾病的条件，如溶菌体储藏病和 糖尿病；例如，阿卡波糖，一种含有假糖的寡糖， 已知能改善胰岛素依赖型糖尿病患者的代谢状况。 综合方法论在关键步骤中涉及刘易斯 C-糖基硝酸硅酯的酸催化缩合反应 硝基甲烷(用于非还原的假二糖)或来自C-硝甲基 含糖基的碳水化合物衍生物(用于还原假二糖) 用于β-假异构体的醋酸盐)或糖基氟(用于α-异构体)， 然后是激进的脱氮和对由此产生的 中间体。海藻糖(α，α)C-类似物的合成 和β)纤维二糖、麦芽糖、乳糖和蔗糖也在计划中。为 1，6-连接的假二糖(葡萄糖和/或半乳糖)的制备 单元)，关键的偶联反应将由硝醛实现 C-糖基硝基甲烷硝酸硅酯的缩合反应 对话糖。将进行结构分析，重点是 没有外在异常效应，以及初步的生化 研究：假二糖对细胞生长的抑制作用 相应的O-二糖的酶解将是 下定决心。

The development of a methodology for the synthesis of "C-disaccharides", a yet unknown class of pseudodisaccharides having a methylene group (CH2) instead of an oxygen atom at the interglycosidic linkage, and the investigation of their biological properties are the principal objectives of the proposed research. Owing to their complete inertness with respect to hydrolysis, these pseudodisaccharides are extremely interesting analogues of the natural disaccharides that are expected to act as potent competitive inhibitors of glycosyl hydrolases. As shown with other carbohydrate derivatives including S-disaccharides, glycosidase inhibitors are not only useful biochemical tools, but have found also important applications in the treatment and the study, under physiological conditions, of metabolic diseases such as the lysozomal storage disease and diabetes; for example, acarbose, a pseudosugar-containing oligosaccharide, is known to improve the metabolic condition of insulin-dependent diabetics. The synthetic methodology involves, in the key steps, the Lewis acid-catalyzed condensation of a silyl nitronate derived from a C-glycosyl nitromethane (for non-reducing pseudodisaccharides) or from a C-nitromethyl carbohydrate derivative (for reducing pseudodisaccharides) with a glycosyl acetate for beta-pseudoanomers) or a glycosyl fluoride (for alpha-anomers), followed by radical denitration and deprotection of the resulting intermediates. The synthesis of the C-analogues of trehalose (alpha,alpha and beta,beta) cellobiose, maltose, lactose, and sucrose is planned. For the preparation of 1,6-linked pseudodisaccharides (gluco and/or galacto units), the key coupling reaction will be achieved by nitroaldol condensation of the silyl nitronate of C-glycosyl nitromethanes with dialdosugars. Structural analysis will be performed, with emphasis on the absence of exo-anomeric effect, as well as preliminary biochemical investigations: the inhibitory effect of the pseudodisaccharides on the enzymatic hydrolysis of the corresponding O-disaccharides will be determined.